Free penicillins and their salts are generally less effective when taken orally than when administered parenterally. Because of inactivation in the stomach and gut, higher doses are required orally than parenterally in order to achieve the same blood levels, and there is a great variation in the ability of individuals to absorb penicillin into the blood by the oral route. Much research has in the past been directed to the discovery of penicillins which are less readily inactivated in the stomach and gut so that a relatively large part of the therapeutic agent administered orally can be absorbed into the blood. This has led to the development of some more highly orally-active penicillins.
When a penicillin arrives in the blood stream, whether by the oral or the parenteral route, some is broken down and the rest is excreted before inactivation. A dose of a sodium penicillin is normally completely eliminated from the body within a few hours of intramuscular injection. The concentration of the penicillin in the blood steadily decreases from its maximum level, and the pencillin may require replenishment by frequent repeated further administration in order to maintain a sufficient concentration until the presence of the therapeutic agent is no longer required. Accordingly research has in the past also been directed to the provision of long-acting preparations which release their penicillin content in such a way as to maintain a relatively high concentration of the therapeutic agent in the blood over a prolonged period. Thus, attempts have been made to solve this problem by means of penicillin salts or other derivatives from which the penicillin is chemically released in the body. It has in practice proved extremely difficult to find derivatives which will break down to release the free penicillin where it is required while at the same time not breaking down in the stomach. For example, many penicillin esters show no substantial therapeutic activity in man, as their hydrolysis to free penicillin in the body proceeds far too slowly.
Probenecid administered concomittantly with ampicillin derivatives has the valuable property of retarding the excretion of the ampicillin derivatives through the kidneys. The use of concomittantly administered probenecid for maintaining an elevated antibiotic level suffers from the disadvantage that several doses are required to build up the probenecid level so that its effect may be observed.
The present invention is directed to the new ampicillin derivatives, probenecidoxymethyl and 1-ethyl esters of ampicillin hydrochloride, which on oral administration are resistant to breakdown in the stomach but beyond the stomach hydrolyze with the release of free ampicillin which is absorbed and remains in the blood stream over a prolonged period by virtue of the fact that sufficient probenecid is formed as a result of the hydrolysis to retard the urinary excretion of ampicillin.